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Last week, President Obama officially announced $100 million in funding for arguably the most ambitious neuroscience initiative ever proposed.

The Brain Research through Advancing Innovative Neurotechnologies, or BRAIN, as the project is now called, aims to reconstruct the activity of every single neuron as they fire simultaneously in different brain circuits, or perhaps even whole brains.

The “next great American project,” as Obama called it, could help neuroscientists understand the origins of cognition, perception, and other enigmatic brain activities, which may lead to new, more effective treatments for conditions like autism or mood disorders and could help veterans suffering from brain injuries.

Big brain science is also on the minds of Europeans; the European Union recently announced a nearly 1.2 billion Euro, 10-year proposal to computationally simulate the human brain from the level of molecules and neurons up through neuronal circuits.  

Various tools—from genetics and molecular biology—have helped researchers understand how neurons behave as individuals. But neuroscientists are now able to study only the activity of a handful of these brain cells at a time using voltage-sensing electrode probes.

Other efforts to map the physical connections in the brain are already under way, but these projects either look at dead brains or provide only a rough, low-resolution view of how regions of the brain communicate. For example, the Allen Institute for Brain Science has developed several so-called Brain Atlases that map the physical connections between neurons in different species’ brains as well as the patterns of unique genetics in each neuron. While these static maps are great to learn about the architecture of the brain, they don’t provide information about how neuron activity leads to brain function.

It’s possible to get a rough view of whole-neural-circuit activity using tools like MRI and EEG, but only at a low resolution. And the behavior of the brain in between these two scales—how thousands or millions of neurons interact to control the behavior of discrete circuits in the brain—has been inaccessible. Scientists don’t yet understand how complex interactions among many neurons at once give rise to neural circuit function.

The BRAIN initiative proposes to develop new technologies that can record the activity from thousands, if not millions or billions, of neurons simultaneously at timescales matching behavior and mental activities. The initiative will likely tackle discrete brain circuits within different species of animals to understand how neurons work together to give rise to behaviors, moods, and other mental phenomena.  

Developing novel technologies will be necessary to achieve the goals of BRAIN, and these will likely take advantage of recent advances in nanotechnology. Existing sensors can record the electrical activity of neurons, but can typically monitor fewer than 100 neurons at a time.

Emerging micro- and nanofabrication techniques could be used to create smaller chips bearing smaller electrical and even chemical probes that would be less invasive. Nanoprobes bearing several dozen electrodes, for instance, could be stacked to probe hundreds of thousands of recording sites and transmit data wirelessly.

Alternatively, nanoparticles carrying molecules that bring them to specific cell types could lodge in cell membranes so surgical placement wouldn’t be necessary. The nanoparticles could also carry molecules that can sense electrical activity, pressure, or even certain chemicals revealing brain activity.

Novel optical techniques could also aid the mapping project. When a neuron fires, the amount of calcium inside cells increases, so many research groups use calcium-sensitive fluorescent dyes to study neuron activity. But this measurement is once removed from the actual electrical activity of the neuron. A voltage-sensitive fluorescent molecule or other imaging agent could provide a more accurate view of activity.

Synthetic biology could be another useful tool. Enzymes that build strands of DNA are sensitive to ion concentration and will introduce more errors into their DNA production in the presence of calcium. As such, these enzymes could be used as sensors for neuron activity. A predetermined DNA sequence could be implanted into neurons and, as it is copied, the resulting strand of DNA would provide a record of the patterns of errors corresponding to patterns of neuron activity. Error-spotted strands from different neurons could later be sequenced.

Researchers sketched out a rough roadmap for the project in a 2012 proposal. The initiative will most likely start with the development of improved calcium-imaging methods for recording neuron firing, followed by voltage-imaging of neuron activity. Since these two methods would look only at surface structures (because light cannot travel far into brain tissue), the third step could be the development of large arrays of nanoprobes.

In the first five years, the initiative may start with small circuits, such as the whole nervous system of the nematode C. elegans (which has only 302 neurons and 7,000 connections) and discrete circuits of the fruit fly brain. Individual circuits in a mouse nervous system, such as that in the retina or olfaction center, could be tackled within 10 years, and within 15 years, scientists may be able to reconstruct the neuronal activity of the entire neocortex of a mouse.

Even without directly exploring the human brain, the resulting insights could have a profound impact on neuroscience and medicine—that is, if everything in this next great American project goes according to plan.

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Tagged: Biomedicine, nanotechnology, brain, DARPA, Barack Obama, NIH, brain activity map, NSF

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